Submissions for variant NM_022124.6(CDH23):c.9326G>A (p.Arg3109His)

gnomAD frequency: 0.00019  dbSNP: rs200188029

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155058	SCV000204742	uncertain significance	not specified	2014-02-04	criteria provided, single submitter	clinical testing	The Arg3109His variant in CDH23 has not been previously reported in individuals with hearing loss, but has been identified in 0.04% (3/8324) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs200188029). Although this variant has been seen in the general p opulation, its frequency is not high enough to rule out a pathogenic role. Compu tational analyses (biochemical amino acid properties, conservation, AlignGVGD, P olyPhen2, and SIFT) do not provide strong support for or against an impact to th e protein. In summary, additional information is needed to determine the clinica l significance of this variant.
Illumina Laboratory Services, Illumina	RCV000369593	SCV000363934	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000277499	SCV000363935	uncertain significance	Usher syndrome type 1D	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV004528888	SCV000363936	uncertain significance	CDH23-related disorder	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245385	SCV001418670	uncertain significance	not provided	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3109 of the CDH23 protein (p.Arg3109His). This variant is present in population databases (rs200188029, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 178314). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDH23 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002484935	SCV002789552	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2021-08-17	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001276926	SCV001463583	uncertain significance	Usher syndrome type 1	2020-09-16	no assertion criteria provided	clinical testing